Small-molecule inhibitors of interleukin-2

Details Small-molecule inhibitors of interleukin-2 Small-molecule inhibitors of interleukin-2

2001-12-17

2004-10-19

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S218000, C514S254050, C514S314000, C514S318000, C540S575000, C544S371000, C546S167000, C546S194000, C546S211000

Reexamination Certificate

active

06806279

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to small-molecule inhibitors of interleukin-2.
2. Description of Related Art
The cytokine interleukin-2 is a principal regulator of the Th1, or cell-mediated, immune response [Waldmann et al., “Contrasting Roles of IL-2 and IL-15 in the Life and Death of Lymphocytes: Implications for Immunotherapy”,
Immunity
, 2001, 14, 105-110]. When the body launches a Th1 response against its own cells, autoimmune diseases (such as rheumatoid arthritis, multiple sclerosis, uveitis, and psoriasis) occur. Similarly, cell-mediated immunity causes rejection of transplanted organs (allograft rejection) and graft-versus-host disease (GVHD), a serious complication that can occur after bone-marrow transplantation.
The IL-2 receptor system (IL-2R) contains three subunits. The dimeric receptor, containing the beta and gamma subunits, is found on most immune cells; IL-2-mediated signaling through this receptor stimulates basal cell growth of T-cells, natural killer cells, and macrophages. During a Th1 immune response, the alpha chain of the IL-2 receptor (IL-2R&agr;) is expressed on the surface of activated T-cells. Binding of IL-2 to this trimeric receptor causes the activated T-cells to proliferate, and this T-cell proliferation is in turn responsible for stimulating the cell-mediated immune response.
Currently used immunosuppressive protocols designed to inhibit allograft rejection and GVHD involve the use of general immunosuppressants such as azathioprine, cyclosporin, rapamycin, tacrolimus, mycophenolate mofetil, and corticosteroids, generally in combinations of two or more of these drugs. All of these can cause toxic side effects to non-lymphoid tissues. It would be desirable to develop inhibitors of the Th1 immune response that selectively block the proliferative activity of IL-2/IL-2R&agr; binding without affecting the role of IL-2 role in basal cell growth, as these selective IL-2R&agr; antagonists should be safer than general inmnunosuppressants.
Recently, two antibodies directed against IL-2R&agr; (basiliximab and daclizumab) have been approved for allograft rejection. Studies have shown that these antibodies provide benefits over the standard three-drug (azathioprione, cyclosporin and mycophenolate mofetil or steroids) regime without some of the side effects of that therapy (Berard et al., “A review of interleukin-2 receptor antagonists in solid organ transplantation”,
Pharmacotherapy
1999, 19, 1127-1137; Nashan, “The interleukin-2 inhibitors and their role in low-toxicity regimens”,
Transplantation Proc
. 1999, 31 (
Suppl.
8A), 23S-26S). However, these antibodies are not orally bioavailable.
Application of new immunosuppressants to autoimmune disease has lagged behind treatments for graft rejection. While autoimmune diseases have diverse manifestations, the up-regulation of the immune response appears to be a common underlying pathology. Important unmet medical needs exist for autoimmune diseases such as rheumatoid arthritis, multiple sclerosis (MS), uveitis, and psoriasis. Several of the therapeutics currently used to treat autoimmune diseases require intravenous, intramuscular or subcutaneous injection, and are thus suboptimal for chronic use. Nevertheless, several ongoing clinical trials are investigating the use of anti-IL-2R&agr; antibodies for multiple sclerosis and other autoimmune diseases. See, for example, Brok et al., “Prophylactic and therapeutic effects of a humanized monoclonal antibody against the IL-2 receptor (daclizumab) on collagen-induced arthritis (CIA) in rhesus monkeys”,
Clin. Exp. Immunol
. 2001, 124, 134-141.
Thus, despite improved therapies for immunosuppression, autoimmune diseases continue to be important pathologies in need of safe and efficacious treatments. To date, no small-molecule IL-2 antagonists have been reported. It would be desirable to develop a small-molecule orally available inhibitor of the IL-2/IL-2R&agr; interaction.
The disclosures of all documents referred to throughout this application are incorporated herein by reference.
SUMMARY OF THE INVENTION
In a first aspect, this invention is compounds of formula I or formula I′
where,
m is an integer selected from 0, 1, and 2;
n and o are integers independently selected from 0 and 1;
A is selected from the group consisting of N and CH;
B is selected from the group consisting of —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—, —CH
2
—CH
2
—NH—, —CH
2
—O—CH
2
—, —CH
2
—S—CH
2
—, —C(═O)—NH—, —C(═O)—CH
2
—, —CH
2
—C(═O)—NH—, —C(═O)—CH
2
—C(═O)—, —C(═O)—NH—CH
2
—, —C(═O)—, —S(═O)—, —S(═O)
2
—, —S(═O)—NH—, —S(═O)
2
—NH—, —S(═O)—CH
2
—, —S(═O)
2
CH
2
—, —S(═O)—CH
2
—NH—, —S(═O)
2
—CH
2
—NH—, —S(═O)
2
—NH—CH
2
—, —CH
2
—S(═O)
2
—NH—, —C(═O)—NH—S(═O)
2
—, —S(═O)
2
—NH—C(═O)—, —C(═O)—CH
2
—S(═O)
2
—, and —S(═O)
2
—CH
2
—C(═O)—;
J is absent or selected from the group consisting of —O—, —S—, —CHR
15
—O—, —CH
2
—CHR
15
—O—, —NH—, —NH—CHR
15
—, —NH—CHR
15
—C(═O)—, —C(═O)—, —CH
2
—, —CHR
15
—CH
2
—NH—, —C(═O)—CHR
15
—, —NH—C(═O)—CH(C
1
-C
6
alkyl)-, —NH—C(═O)—CH(C
3
-C
12
cycloalkyl)-, —CH
2
—CH
2
—, —CH
2
—NH
2
—, —CH
2
—NH
2
—C(═O)—, —CH
2
—NH
2
—C(═O)—C
1
-C
6
alkyl-, —CH
2
—NH
2
—C(═O)—CH(C
3
-C
12
cycloalkyl)-, and —C(═O)—CHR
15
—NH—; or
B—J is selected from the group consisting of —C(═O)—CH
2
—NH—C(═O)—CH(C
1
-C
6
alkyl, —C(═O)—CH
2
—CH
2
—NH—C(═O)—CH(C
3
-C
12
cycloalkyl)-, —C(═O)—NH—(C
2
-C
6
alkyl), —S(═O)
2
—NH—(C
2
-C
6
alkyl)-, —C(═O)—NH—, —S(═O)
2
—NH—, —C(═O)—CH— and —S(═O)—CH
2
—,
L is selected from the group consisting of —O—, —CH
2
—O—, —O—CH
2
—, —CH
2
—CH
2
—O—, —O—CH
2
—CH
2
—, —CH
2
—O—CH
2
—, —CH
2
—S—CH
2
—, —C(═O)—NH—, —O—C(═O)—NH—, —CH
2
—C(═O)—NH—, —C(═O)—CH
2
—NH—, —C(═O)—NH—CH
2
—, —NH—C(═O)—, NH—C(═O)—O—, —NH—CH
2
—C(═O)—, —NH—C(═O)—CH
2
—, —CH
2
—NH—C(═O)—, —NH—C(═O)—NH—, —NH—S(═O)
2
—NH—, —NH—S(═O)
2
—, —NH—S(═O)
2
—CH
2
—, —CH
2
—NH—S(═O)
2
—, —S(═O)
2
—NH—, —S(═O)
2
—NH—CH
2
—, —CH
2
—S(═O)
2
—NH—, —C(═O)—NH—S(═O)
2
—, —S(═O)
2
—NH—C(═O)—, —CH
2
—NH—, —CH
2
—CH
2
—NH—, —NH—CH
2
—, —NH—CH
2
—CH
2
—, —CH
2
—NH—CH
2
—, —C≡C—, —CH
2
—C≡C—, —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—, —CH
2
—CH═CH—, CH═CH—CH
2
—, and —CH═CH—;
M is selected from the group consisting of R
9
and an optionally substituted group selected from phenyl, naphthyl, C
3
-C
7
-cycloalkyl, and heterocyclyl, the heterocyclyl group being aliphatic, partially unsaturated, or aromatic, and containing 1 or 2 rings each containing 5-7 ring atoms of which 0-3 are hetero atoms selected from N, O and S, provided that at least one ring contains a heteroatom and where any ring carbon or sulfur may optionally be oxidized, the optional substituents being up to three groups selected from R
1
, R
2
and R
9
; or
M is selected from the group consisting of
Q is selected from the group consisting of —C(═O)OR
16
, —C(═O)—NH—C(═O)—CF
3
, —C(═O)—NH—S(═O)
2
—R
2
, —C(═O)—NR
1
—OH, 5-oxo-4,5-dihydro[1,2,4]oxadiazol-3-yl, and tetrazolyl;
X is A when n is 1, and is CH, N, O or S when n is 0;
R
1
is selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, halo-(C
1
-C
6
)alkyl, and (C
3
-C
6
)cycloalkyl;
R
2
, R
3
and R
5
are individually selected from the group consisting of hydrogen, cyano, nitro, phenyl, phenoxy, benzyl, C
1
-C
6
alkyl, halo, halo-C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, C
1
-C
6
alkoxy, hydroxy, C
1
-C
2
alkoxy-methoxy, hydroxy-C
1
-C
6
alkyl, formyl, C
1
-C
6
alkylcarbonyl, amino, C
1
-C
6
alkylamino, aminocarbonyl, C
1
-C
6
alkylaminocarbonyl, formylamino, and C
1
-C
6
alkylcarbonylamino, where any alkyl or phenyl may optionally be substituted with halo or Q;
R
4
selected from the group consisting of R
2
and
 where Ar is a homo- or he

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